J. Org. Chem. 1994,59, 6014-6017
6014
Intramolecular C-H Insertion by an Alkylidene Carbene: Diastereoselective Synthesis of a Taxol A Ring Synthon Douglass F. Taber,* Rainer Walter, and Robert P. Meagley Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716 Received January 19, 1994@
The first stage in a proposed total synthesis of the clinically effective anticancer agent taxol 1 is reported. A key step in this synthesis is the development of a new procedure for the generation and cyclization of the alkylidene carbene derived from ketone 9, to give cyclopentene 10 (formation of three new carbon-carbon bonds) in 72% yield. Ozonolysis of 10 followed by aldol condensation furnished the crystalline cyclohexenone 4. Taxol (11, isolatedl originally from the bark of the Pacific yew Taxus brevifolia, has demonstrated substantial clinical activity.2 We are currently engaged in a total synthesis of 1,3,4focusing on the possibility of an internal Diels-Alder cycloaddition (321 2) to construct the tricyclic carbon skeleton. We report a diastereoselective synthesis of 4, a sufficient A-ring synthon5 for the preparation of 3. The key step in the synthesis of 4 is construction of the quaternary stereogenic center by intramolecular C-H insertion of an intermediate alkylidene carbene. Background. Pioneering studies of the Diels-Alderbased A ABC assembly of the taxane skeleton have In both cases, a strategem had to be adopted to ameliorate the rapid increase in nonbonding interactions across the forming eight-membered ring, that otherwise would obviate cycloaddition. Desiring a mini-
0 . u
-
Ph
-
Abstract published in Advance ACS Abstracts, September 1,1994. (1)Wani, M.-C.; Taylor, H. L.; Wall, M. E.; Coggon, P.; McPhail, A. T. J . Am. Chem. SOC.1971,93, 2325. (2) Suffness, M. Annual Reports in Medicinal Chemistry; Academic Press: New York, 1993; Vol. 28, Chp. 32. (3) For the first synthesis of a taxane diterpene, see: Holton, R. A.; Juo, R. R.; Kim, H. B.; Williams, A. D.; Harusawa, S.; Lowenthal, R. E.; Yogai, S. J . Am. Chem. SOC. 1988,110, 6558. (4)For synthetic approaches to the tricyclic taxol core, see: (a) Sakan, K; Craven, B. M. J . Am. Chem. SOC. 1983,105,3732.(b) Kende, A. S.; Johnson, S.; Sanfilippo, P.; Hodges, J. C.; Jungheim, L. N. J . Am. Chem. SOC.1986,108,3513. (c) Bonnart, R. V.; Jenkins, P. R. J. Chem. SOC.,Perkins Trans. 1 1989,413. (d) Swindell, C. S.; Patel, B. P. J . Org. Chem. 1990, 55, 3. (e) Yadav, J . S.; Ravishankar, R. Tetrahedron Lett. 1991,32,2629. (f) Blechert, S.; Kleine-Klausing, A. Angew. Chem. Int. Ed. Engl. 1991,30,412.(g) Jackson, R. W.; Higby, R. G.; Shea, K. J. Tetrahedron Lett. 1992,33,4695.(h) Hitchcock, S. A,; Pattenden, G. Tetrahedron Lett. 1992,33,4843. (i) Wender, P. A.; Mucciaro, T. P. J . Am. Chem. SOC.1992, 114, 5878. (j) Kataoka, Y.; Nakamura, Y.; Morihara, K.; Arai, H.; Horiguchi, Y.; Kuwajima, I. Tetrahedron Lett. 1992,33,6979. (k) Paquette, L. A.; Zhao, M. J. Am. Fallis, A. G. Tetrahedron Lett. Chem. SOC.1993,115,354. (1) Lu, Y.-F.; 1993,34, 3367. (m) Wang, Z.; Warder, S. E.; Perrier, H.; Grimm, E. L.; Bernstein, M. A. J . Org. Chem. 1993, 58, 2931. (n) Kress, M. H.; Reul, R.; Miller, W. H.; Kishi, Y. Tetrahedron Lett. 1993,34, 5999. (0) Nicolaou, K. C.; Yang, Z.;Sorenson, E. J.;Nakada, M. J. Chem. SOC., Chem. Commun. 1993,1024. ( 5 ) For synthetic approaches to the taxol A ring, see: (a) Lin, J.; Nikaido, M. M.; Clark, G. J. Org. Chem. 1987,52,3745. (b) Petterson, L.; Frejd, T.; Magnusson, G. Tetrahedron Lett. 1987, 28, 2221. (c) Snider, B. B.; Allentoff, A. J. J . Org. Chem. 1991,56,321.(d) Benchikh le-Hocine, M.; Do Khac, D.; FBtizon, M; Guir, F.; Guo, Y.; Prang6, T. Tetrahedron Lett. 1992, 33, 1443. (e) Queneau, Y.; Krol, W. J.; Bornmann, W. G.; Danishefsky, S. J. J. Org. Chem. 1992,57,4043. (0 Oh, J.; Choi, J.-R.; Cha, J . K. J . Org. Chem. 1992, 57, 6664. (g) Nicolaou, K. C.; Hwang, C.-K.; Sorenson, E. J.; Clairborne, C. F. J. Chem. SOC.,Chem. Commun. 1992,1117. (h) Golinski, M.; Vasudevan, S.; Floresca, R.; Brock, C. P.; Watt, D. S. Tetrahedron Lett. 1993,34, 55. (i)Arseniyadis, S.;Yashunsky, D. V.; Pereira de Freita, R.; Munoz Dorado, M.; Toromanoff, E.; Potier, P. Tetrahedron Lett. 1993,34,1137. (j) Di Grandi, M. J.; Jung, D. K.; Krol, W. J.; Danishefsky, S. J. J . Org. Chem. 1993, 58, 4989. (k) Parsons, P. J.; Stefinovic, M. Synlett 1993, 931.
'
1
1
@
-
O
a
'
I
-
3a = a-alkyl
O
yo b
OBn 4
3b = Palkyl
mally-substituted synthetic intermediate, we have pursued detailed conformational analysis of a series of substituted trienes. This led us to the discovery that the lowest energy conformation of acetonide 3a is wellaligned for cycloaddition. Although 3b is in fact more stable than 3a, the calculated6energy difference between 3a and 3b is only 1.8 kcal/mol. Under equilibrating conditions at 200 "C (the usual temperature for such unactivated cycloadditions), there should be a sufficient steady state concentration of 3a for the cyclization to proceed. The cyclization itself is calculated7t o be exothermicby about 18kcal/ mol. Enone 4 appeared to be a suitable precursor for the preparation of 3. We report here a diastereoselective (6) Shortly affer this work was submitted, the first two total syntheses of taxol appeared: (a) Holton, R. A.; Kim, H.-B.; Somoza, C.; Liang, F.; Biediger, R. J.; Boatman, P. D.; Shindo, M.; Smith, C. C.; Kim, 5.; Nadizadeg, H.; Suzuki, Y.; Tao, C.; Vu, P.; Tang, S.;Zhang, P.; Murthi, K. K.; Gentile, L. N.; Liu, J. H. J . Am. Chem. SOC.1994, 116, 1599. (b) Nicolau, K. C.; Yang, Z.; Liu, J. J.; Ueno, H.; Nantermet, P. G.; Guy, R. IC;Claiborne, C. F.; Renaud, J.; Couladouros, E. A.; Paulyannan, K.; Sorenson, E. J. Nature, 1994, 367, 630. (7) Calculations were carried out using MOPAC AM1' as implemented on a Tektronix CAChe workstation. (8) Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J . J. P. J.Am. Chem. SOC.1985,107,3902.
0022-326319411959-6014$04.50100 1994 American Chemical Society
J. Org. Chem., Vol. 59, No. 20, 1994 6015
Diastereoselective Synthesis of a Tax01 A Ring Synthon
anion 12a. It is assumed that condensation of 12 with a ketone proceeds through 13, which then thermally (but well below ambient temperature) a-eliminates, via 14. A limitation to this method for the generation of alkylidene carbenes from ketones is the multistep synthesis of 12a.
Scheme 1
0
BnO
OH
5
BnO
62%
4-DMAP, Et20 72%
6
+ X+N2 1. LDA x 2.2, -78’ -> 60’
BnO
2.
11
61%
BnO 8
1. NaBH4 2. K20s02(0H), (cat) K3Fe(CN)s tBuOH I H20
-
\
b
,o
* DME
3. acetonel Na2S0, I H2S04
-40’ -> RT
4. Swem
BnO 9
42%
72%
1. 03:Ph3P 2. K O H I M O H OBn
3. DMSO, 150’ B”O
10
65%
14
12b, X= (CH&SI
ca4,A
7
12a, X=(CH30)2P(0) 13
4
synthesis that is straightforward enough to allow the preparation of gram quantities of the crystalline enone 4. Preparation of Alkene 8. The key intermediate for the synthesis of 4 was the alkene 8 (Scheme 1).Aldehyde 59was readily prepared on a substantial scale using the P205/DMS0oxidation procedure that we have reported.1° Grignard addition led to the unstable alcohol 6.11 We carried 6 on to 8 using the Wilson12 modification of the Carroll rearrangement. Intramolecular C-H Insertion by an Alkylidene Carbene. To set the stage for intramolecular C-H insertion (Scheme l),we first effected catalytic osmylation13of the alkene 8. We found that it was important to first reduce the ketone, since the osmylation proceeded more efficently on the secondary alcohol. In practice, it was most expedient to carry out the four steps (reduction, dihydroxylation, protection, and oxidation) without purificaton of the intermediates. With ketone 9 in hand, we were prepared to investigate procedures for the generation of the alkylidene carbene. Intramolecular C-H insertion into a methine by an intermediate alkylidene carbene was first demonstrated by Gilbert,l4” using dialkyl diazomethyl phosphonate (9) For previous preparations of aldehyde 6, see: (a) Amdt, H. C.; Carroll, S. A. Synthesis 1979,202. (b) Jhbayashi, Y.; Ito,Y.; Terashima, S. Tetrahedron 1992, 48, 55. (10)Taber, D. F.;h e d i o , J. C., Jr.; Jung, IC-Y. J.Org. Chem. 1987, 52, 5621. (11)Hart, D. J.; Yang, T.-K. J. Org. Chem. 1986, 50, 235. (12) Wilson, S. R.; Price, M. F. J. Org. Chem. 1984, 49, 722. (13) Minato, M.; Yamamoto, K.; Tsuji, J. J . Org. Chem. 1990, 55, 766. (14) For alkylidene carbene generation using dimethyl (diazomethyl)phosphonate, see: (a)Gilbert, J . C.; Giamalva, D. H.; Weerasooriya, U. J . Org. Chem. 1983, 48, 5251. (b) Gilbert, J. C.; Giamalva, D. H.; Baze, M. E. J . Org. Chem. 1986, 50, 2557.
A variation on this approach was recently reported by 0hira,l5using the anion of (trimethy1silyl)diazomethane. An obvious advantage is that the TMS diazomethane is commercially available.16 Our early investigations using the Ohira protocol, in THF, were not successful. We were gratified, however, to find that the use of dimethoxyethane as solvent was much more rewarding. Exposure of ketone 9 to the anion of TMS diazomethane in DME/ hexane led to cyclopentene 10 in 72%yield. It should be noted that alternative cyclopentenes could have been formed in the cyclization, by insertion into a C-H bond of one of the methyl groups. As has been observed before,14*a methine is much more reactive than a methyl group. In this particular case, the methine is further activated by a-oxygen substitution.17 Ozonolysis of 10 followed by aldol condensation provided a small quantity of enone 4 and a much larger proportion of a more polar substance that was deduced to be the P-hydroxy ketone. Brief warming of the crude aldol reaction mixture in DMSO gave the nicely crystalline enone 4 in 65% yield from 10. Conclusion. A particular appealing aspect of the taxol A ring preparation reported here is that application of asymmetric dihydro~ylationl~ to 8 should lead to symchiralZ04. The DME modification of the GilbertOhira cyclization reported here should make intramolecular C-H insertion by an alkylidene carbene a generally useful procedure in organic synthesis. Experimental Sectied 4-Methyl-l-(phenyImethoxy)-3-penten-2-01(6). CHzClz (500 mL), PzOs (51.0 g, 360 mmol), and DMSO (31.2g, 400 m m ~ lwere ) ~ combined sequentiallywith mechanical stirring at rt. The mixture was cooled in an ice-water bath, and then (15)For alkylidene carbene generation using (trimethylsily1)diazChem. omethane, see: Ohira, S.; Okai, K.; Moritani, T. J. Chem. SOC. Commun. 1992, 721. (16) (Trimethylsilyl)diazomethane,purchased from Aldrich, was contaminated with a 29% impurity, lH NMR (6) = 2.63. We separated the (trimethylsily1)diazomethane from solvent hexane by spinning band distillation. This did not, however, remove the impurity. (17) Adams, J.; Frenette, R. Tetrahedron Lett. 1987,28, 4773. (18) For dehydration on warming in DMSO, see: (a) Traynelis, V.; Hergenrother, W. L.; Hanson, H. T.; Valicenti, J. A. J. Org. Chem. 1964, 29, 123. (b) Ichihara, A.; Miki, M.; Tazaki, H.; Sakamura, S. Tetrahedron Lett. 1987,28, 1175. (19) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hartung, J.; Jeong, K.-S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.M.; Xu, D.; Zhang, X.-L. J . Org. Chem. 1992,57,2768. (b) The ligand/ potassium osmate/potassium ferricyanide mixtures are available commercially from the Aldrich Chemical Co. as AD-mix a and ADmix P. (20) For the use of “symchiral” to mean “having high enantiomeric purity”, see: (a) Taber, D. F. Chem. Eng. News 1991,August 19,5. (b) Magar, S. S.; Fuchs, P. L. Tetrahedron Lett. 1992,33, 745. ( c ) Taber, D. F.; Deker, P. B.; Silverberg, L. J . J . O g . Chem. 1992,57, 5990. (21)For a general experimental procedure, see: Taber, D. F., Bhamidipati, R. S.; Thomas, M. L. J . Org. Chem. 1994, 59, 3442.
6016
J. Org. Chem., Vol. 59,No. 20, 1994
Taber e t al.
(cm-l) 2961,2870, 1717, 1454, 1361; MS (mlz)231 (6), 188 (6), 2-(phenylmethoxy)ethanolzz(32.0 g, 210 mmol) in CHzClz (25 164 (2), 91 (100); HRMS calcd for C16H2202 246.1620, found mL) was added dropwise over 10 min. The ice bath was 246.1613. removed, and stirring was continued for 3 h. The mixture was (R*,R*)-2,2-Dimethyl-4-( l,l-dimethyl-3-oxobutyl)-5cooled in an ice-water bath, and then Et3N (101.2 g, 1.0 mol) [(phenylmethoxy)methyl]-1,3-dioxolane(9). Ketone 8 was added dropwise over 30 min. After stirring for an (246 mg, 1.00 mmol) was dissolved in ethanol (20 mL), and at additional 2 h, 10% aqueous HCl(150 mL) was added dropwise 0 "C sodium borohydride (190 mg, 5 mmol) was added. After over 30 min. After stirring for an additional 2 h, the layers completion of the reaction (TLC), the mixture was acidified were separated, and the organic layer was washed with water with 10% aqueous HC1. Water (20 mL) was added, and the (3 x 200 mL) to remove excess DMSO. The organic layer was reaction mixture was extracted with EtOAc. The organic layer dried (NazSOJ, concentrated, and distilled bulb-to-bulb (bpo.5 was dried (NazS04), concentrated, and filtered through silica (bath) = 80-95 "C) to yield 22.9 g (74% yield) of aldehyde 5 gel to give 225 mg (0.91 mmol, 91%) of the corresponding as a colorless oil. alcohol. The Grignard reagent prepared from l-bromo-2-methyl-lAn amount of 8.43 g (34 mmol) of this alcohol was dissolved propene (25.7 g, 190 mmol) and Mg (4.6 g, 190 mmol) in THF in tert-butyl alcohol (135 mL). This solution was added to a (50 mL) was stirred vigorously and chilled in an ice-water solution of potassium ferricyanide (33.6 g, 102 mmol), potasbath. Aldehyde 5 (25.7 g, 170 mmol) in THF (80 mL) was sium carbonate (14.1 g, 102 mmol), and potassium osmate added dropwise over 30 min. Saturated aqueous NH&l(lOO (Colonial Metals; 68 mL of a 0.025 M solution in 1:3 watermL) was added, followed by sufficient water t o dissolve the tert-butyl alcohol, 1.7 mmol) in water (110 mL). The mixture solids. The mixture was extracted with EtOAc (2 x 100 mL). was stirred vigorously at rt for 24 h. Saturated aqueous The organic extract was washed with saturated aqueous NaC1, sodium sulfite was added, and the mixture was stirred for dried (NazSOd), and concentrated. The residue was chromatoanother 1 h. After extraction with EtOAc, the combined graphed to yield 21.7 g (105 mmol, 62%) of alcohol 6 as a organic layers were washed with saturated aqueous sodium colorless oil, TLC Rf (20% EtOAc/petroleum ether) = 0.35. sulfite, dried over NazS04, and concentrated. Chromatography Spectroscopic data were congruent with those reported.1° yielded the corresponding triol (5.34 g, 18.5 mmol, 56%) as a 4-Methyl-l-(phenylmethoxy)-3-penten-2-yl 3-Oxobumixture of diastereomers. tanoate (7). Alcohol 6 (17.6 g, 85.3 mmol) in ether (170 mL) Sodium sulfate (10.2 g, 72 mmol) followed by 10 drops of was chilled in an ice-water-salt bath to an internal temperaconcentrated sulfuric acid were added to a solution of the ture of -12 "C. Diketene (Aldrich; 50% in acetone, 17 mL, mixture of triols (5.04 g, 17.9 mmol) in dry acetone (170 mL). 102 mmol) was added with stirring, followed by 4-(dimethylThe mixture was stirred for 18 h, after which the acid was amino)pyridine (104 mg, 0.85 mmol). The mixture was stirred neutralized with potassium carbonate. After filtration from and allowed t o come to rt over 18 h. Aqueous NaOH (0.1%, the solids, the solvent was removed in uucuo to give the crude 50 mL) was added, and then the pH of the solution was acetonide (5.41 g) as a mixture of diastereomers. adjusted t o 8 with 1%aqueous NaOH. The layers were DMSO (3.05 mL, 43.0 mmol) was added slowly at -60 "C separated, and then the organic layer was washed sequentially with stirring to a solution of oxalyl chloride (2.03 mL, 23 mmol) with 0.1% aqueous NaOH (50 mL) and saturated aqueous in 100 mL of CH2C12. After an additional 30 min, a solution NaCl (50 mL), dried (NazSOd), concentrated, and chromatoof the mixture of acetonides (5.41 g) in CHzClz (25 mL) was graphed t o give ester 7 (19.0 g, 65.4 mmol, 77% yield): TLC added dropwise over an additional 30 min. After a further 30 Rf (20% EtOAclpetroleum ether) = 0.48, as a colorless oil; 'H min at -60 "C, triethylamine (12.5 mL, 89.5 mmol) was added NMR (6) 1.12-1.93 (m, 6 H), 2.21 (s, 3 H), 3.41 (s, 2 H), 3.48 dropwise, after which the reaction mixture was allowed to (dd, J = 10.8 Hz, J = 3.9 Hz, 1H), 3.57 (dd, J = 10.8 Hz, J = warm slowly t o rt. Water (20 mL) was added, the layers were 7.3 Hz, 1H), 4.51 (d, J = 12.0 Hz, 3. H), 4.55 (d, J = 12.0 Hz, separated, and the aqueous layer was extracted with CHzClz lH), 5.13 (m, 1 H), 5.7 (m, 1 H), 7.3 (m, 5 H); Enol (ca. 18%) (2 x 20 mL). The combined organic extract was dried (Naz(partial) 1.93 (s, 3 H), 5.00 (9, 1 H), 12.12 (s, 1 H); 13C NMR so4), concentrated, and chromatographed to give the ketone (6) down 18.4, 25.6, 29.7, 71.1, 120.0, 127.4, 128.2; up 50.2, 9 (4.78 g, 14.9 mmol, 83%, 42% from 81, TLC Rf(lO% EtOAcl 71.3, 72.9, 137.8, 139.5, 166.3, 200.3; IR (cm-') 2931, 2860, petroleum ether) = 0.33, as a light yellow oil: lH NMR (6) 1740, 1717, 1645; MS (mlz, %) 260 (0.51, 188 (51, 169 (12), 91 0.99 (9, 3H), 1.00 (s, 3H), 1.36 (s, 3H), 1.41 (s, 3H), 2.09 (s, 3H), 2.33 (d, J = 15.4Hz, lH), 2.52 (d, J = 15.4 Hz, lH), 3.52(100); HRMS calcd for C17H2204 290.1518, found 290.1520. 3.55 (m, 2H), 3.81 (d, J = 7.7 Hz, lH), 4.00-4.07 (m, lH), 4.55 (E)-4,4-Dimethyl-7-(phenylmethoxy)-5-hepten-2-one (8). (d, J = 12.3 Hz, lH), 4.61 (d, J = 12.3 Hz, lH), 7.25-7.35 (m, n-BuLi (58 mL of 2.3 M in hexane, 133 mmol) was added 5H); 13CNMR (6) down 22.1, 23.4, 26.9, 27.0, 32.2, 76.6, 83.3, dropwise over 15 min, with stirring and cooling in an ice127.5, 127.6, 128.2; up 35.4, 51.2, 72.5, 73.3, 108.7, 137.9, water bath, to diisopropylamine (20.3 mL, 145 mmol) in THF 208.2; IR (cm-l) 2985, 2934, 2876, 1716, 1379, 1368; MS (mlz, (190 mL). After stirring for an additional 45 min, the mixture %) 305 (5), 262 (61,141 (21),91(100);HRMS calcd for C18H2504 was cooled to -78 "C, and then ester 7 (17.5 g, 60.3 mmol) in (M' - CH3) 305.1752, found 305.1746. 60 mL THF was added dropwise at a rate such that the (R*,S*)-3,3,7,9,9,-Pentamethyl-5-[ (pheny1methoxy)internal temperature did not exceed -65 "C. The mixture was methyl]-2,4-dioxaspiro[4.4]non-6-ene (10).n-BuLi (6.7 mL stirred for an additional 18 h with warming to rt and then of 2.38 M in hexanes, 16.0 mmol) was added dropwise over 5 maintained at 60 "C for 2 h. The mixture was concentrated min t o (trimethy1)silyldiazomethane(Aldrich, 2.0 M in hexon the rotary evaporator and then partitioned between 0.1 N anes, 8.0 mL, 16.0 mmol) in 20 mL of DME at -78 "C. The aqueous NaOH and EtOAc. The organic layer was discarded. cooling bath was removed, and the heterogeneous mixture was The aqueous layer was acidified with 10% aqueous HC1 and stirred until it becomes a clear amber. The mixture was extracted with EtOAc (2 x 50 mL). The organic extract was chilled in a -40 "C bath, and then ketone 9 (1.23 g, 3.84 mmol) dried (Na2S04) and concentrated. The residue was taken up in 4 mL of DME was added dropwise over 5 min. The mixture in ccl4 (250 mL), and the solution was maintained at reflux was stirred and allowed to come to rt over 4 h. Water (10 mL) for 4 h. The mixture was concentrated and the residue was was added, and the mixture was stirred for an additional 10 chromatographed to yield 9.09 g (36.9 mmol, 61% yield) of min and then partioned between EtOAc and water. The ketone 8 as a pale yellow oil: TLC Rf (15% EtOAc/petroleum organic extract was dried (Nad.304) and concentrated, and the ether) = 0.43; 'H NMR (6) 1.13 (9, 6H), 2.08 (s, 3 H), 2.24 (9, residue was chromatographed to give cyclopentene 10 (876 mg, 2H), 3.99 (dd, J = 6.0 Hz, J = 1.2 Hz, 2H), 4.49 ( 8 , 2H), 5.61 (dt,J=15.7Hz,J=6.1Hz,1H),5.83(bd,J=15.7Hz,1H),2.77 mmol, 72% yield) as a colorless oil: TLC Rf (5%EtOAc/ petroleum ether) = 0.35; lH NMR (6) 0.94 (s,3H), 1.10 (s,3H), 7.26-7.35 (m, 5H); 13CNMR (6) down 27.2,32.0, 122.9, 127.4, 1.35 ( 8 , 3H), 1.45 (s, 3H), 1.70 (d, J = 0.9 Hz, 3H), 1.84 (bd, J 127.7, 128.3, 142.4; up 35.5, 55.1, 70.8, 71.9, 138.4, 207.6; IR = 15.9 Hz, lH), 2.25 (bd, J = 15.9 Hz, lH), 3.46 (dd, J = 10.6 Hz, J = 2.3 Hz, lH), 3.54 (dd, J = 10.6 Hz, J = 7.5 Hz, lH), 4.20 (dd, J = 7.5 Hz, J = 2.3 Hz, lH), 4.47 (d, J = 12.4 Hz, (22) Butler, C. L.;Renfrew, A. G.;Clap, M.J.Am. Chem. SOC.1938, 60, 1472. lH), 4.68 (d, J = 12.4 Hz, lH), 5.27 (m, lH), 7.25-7.34 (m,
Diastereoselective Synthesis of a Tax01 A Ring Synthon
J. Org. Chem., Vol. 59,No. 20,1994 6017
5H);13CNMR (6)down 17.2,24.0,25.7,26.6,28.9,77.6,125.0,matographed t o give ketone 4 (593mg, 1.79mmol, 65% yield) 127.4, 127.6,128.2;up43.1,51.0,70.6,73.2,95.2, 107.1,138.1, as a colorless oil: TLC Rf(lO% EtOAdpetroleum ether) = 0.45. This material crystallized from petroleum ether in the freezer 1453;MS (mlz,%) 316 (21, 144.2:IR (cm-l) 2983,2934,2872, to give colorless needles, mp = 52-53 "C; 'H NMR (6) 1.01(s, 215 (4),149 (13), 137 (141,134 (16),125 (38),109 (261,104 3H),1.14(8, 3H),1.43(8, 3H),1.49(8, 3H),2.29(d, J = 16.3 (47),91 (100);HRMS calcd for CzoHz803 316.2038,found Hz,lH),2.50(d, J = 16.3Hz,lH),3.51(dd, J = 10.5Hz,J = 316.2042. lH),4.40(R*,S*)-5-[(Phenylmethoxy)methyll-3,3,10,l0-tetra- 3.65Hz, lH),3.64(dd, J = 10.5Hz, J = 6.2Hz, 4.42(m, lH),4.47(d, J = 12.1Hz, lH),4.60(d, J = 12.1Hz, methyl-2,4-dioxaspiro[4.5ldec-6-en-8-one (4). Ozone in 1H),5.96(d,J=10.3Hz,1H),6.62~d,J~10.3H~,1H),7.27oxygen was bubbled through a solution of cyclopentene 10(876 7.34(m, 5H);13C NMR (6) down 24.0,24.7,26.5,29.0,78.1, mg, 2.77mmol) in CHzClz (10mL) at -78 "C until the solution 73.5, 76.5,83.7, 127.7,128.3,128.7, 146.7;up 38.3,50.0,69.6, was faintly blue (15min). The mixture was flushed with Nz 108.4,137.3,198.6;IR (cm-') 2922,2872,1683;MS (mlz, %) to dispel the blue color, and then triphenylphosphine (800 mg, 330(11,315 (4),216 (41,183 (13),180(24),123 (241,91 (100); 3.05mmol) was added and the mixture was allowed to warm HRMS calcd for C&&4 330.1831, found 330.1849. to rt over 18h. The mixture was concentrated, and the residue was taken up in a solution of KOH (171mg, 3.05mmol) in water (10mL). After the yellow solution had been stirred for Acknowledgment. We thank the NIH (GM46762) 90 min, the mixture was adjusted t o pH = 7 by the addition for support of this work. of 1 N aqueous HCl and partioned between EtOAc and water. The organic layer was thoroughly dried (NazSO4) and concentrated. The residue was taken up in DMSO (20 mL), and the resulting solution was maintained at 150"C for 90min. After cooling, the mixture was diluted with water (100mL) and extracted with EtOAc (2x 20 mL). The organic extract was dried (NaZS04) and concentrated, and the residue was chro-
Supplementary Material Available: lH and I3C spectra for compounds 4 and 7-10 (10 pages). This material is contained in libraries on microfiche, immediately follows this article in the microfilm version of this journal, and can be ordered from the ACS; see any current masthead page for ordering information.
